Novel sulfonylureas



United States Patent 3,155,721 NOVEL SULFONYLUREAS Jack Mills andFrederick J. Marshall, Indianapolis, Ind., assignors to Eli Lilly andCompany, Indianapolis, Ind, a corporation of Indiana No Drawing. FiledNov. 30, 1961, Ser. No. 156,159 2 Claims. (Cl. 260-553) This inventionrelates to certain novel hypoglycemic agents of the sulfonylurea classand to the control of diabetes mellitus therewith.

The compounds provided by this invention can be represented by theformula wherein R is 2-bicyclo[2.2.1]heptyl or 2-bicyclo[2.2.l]heptylmethyl. The compounds defined by the above formula areN-p-ethylphenylsulfonyl-N'-2-bicyclo[2.2.1] heptylurea and N pethylphenylsu1fonyl-N'-2-bicyclo [2.2.1]heptylmethylurea.

The incorporation of the bicyclo[2.2.l]heptyl orbicyclo[2.2.1]heptylmethyl group into certain sulfonylureas confers anunexpectedly high order of antidiabetic efficacy upon the compounds.This is advantageous not only because it makes possible the use of dosesof the compounds lower than those employed with other clinically usefulsulfonylureas, but also because it tends to decrease the frequency andseverity of the side eilects which may be manifested in some degree insome cases with this class of therapeutic agents.

Various methods known in the art can be employed for the preparation ofthe compounds of this invention. One preferred method comprises theinteraction of ethyl- N-p-ethylphenylsulfonylcarbarnate with2-bicyclo[2.2.1] heptylamine or 2-bicyclo[2.2.11-heptylmethylamine toform a salt and the pyrolysis of the salt by heating at itsdecomposition point. The latter step is preferably carried out in aninert solvent such as toluene, xylene or the like. The desired productis readily recovered from the reaction medium by employing standardtechniques.

Other methods may also be employed for the preparation of the instantcompounds. Thus, for example, 2- bicyclo [2.2.1]heptylisocyanate or2-bicyclo[2.2.1]heptylmethylisocyanate can be treated withp-ethylphenylsulfonamide in the presence of an alkali-metal carbonate toproduce the desired sulfonylurea. Additionally, there are available themethods employing the reaction of p-ethylphenylsulfonamide with2-bicyclo[2.2.lJheptylurethane or 2-bicyclo[2.2.1Jheptylmethylurethaneand the reaction of p-ethylphenylsulfonylisocyanate with2-bicyclo[2.2.1] heptylamine or 2-bicyclo[2.2.IJheptylmethylamine. Stillanother method utilizes the pyrolysis in the presence of the appropriateamine of a diphenylsulfonylurea prepared from p-ethylphenylsulfonamideand phosgene.

The cationic salts of these compounds can be prepared by treating thesulfonylureas with a suitable base or basic salt, as for exampleammonium hydroxide, magnesium hydroxide, potassium hydroxide, sodiumcarbonate, and the like. Among the preferred nontoxic cationic salts arethe sodium, potassium, calcium, magnesium, and ammonium salts.

The sulfonyl ureas of this invention and their nontoxic cationic saltsare White, high-melting solids, the former 3,155,721 Patented Nov. 3,1964 crystallizing readily from ethanol. The sulfonylureas are solublein the common organic polar solvents, while their salts are soluble tosome extent in aqueous-organic solvent mixtures.

The compounds of this invention are orally effective hypoglycemic agentsand are therefore useful in the treatment of diabetes. Thus, the bloodsugar level of depancreatized dogs can be regulated by the oraladministration to these animals of the drugs. Of even greatersignificance is the fact that oral administration of daily doses ofbetween about 50 mg. and 1500 mg. of the compounds will provide adequatecontrol of the blood sugar levels of diabetic humans.

Any of the customary oral dosage forms are suitable for theadministration of the compounds of this invention, but compressedtablets or filled capsules, containing the desired amount of drugtogether with the customary pharmaceutical exciptients, are preferred.Thus, for example, a mixture of starch, magnesium stearate, granulargelatin and N-p-ethylphenylsulfonyl N'-2-bicyclo[2.2.1]heptylurea can becompressed into scored tablets of a size such that each tablet containsmg. of the active medica ment.

The operation of the invention is illustrated in the following specificexamples.

Example I A toluene suspension of the N-p-ethylphenylsulfonylcarbamatesalt of 2-bicyclo[2.2.1]heptylamine was prepared by mixing 55 g. ofethyl N-p-ethylphenylsulfonylcarbamate and 40 g. of the amine in 500 ml.of toluene. The mixture was heated at reflux temperature for five hoursin order to pyrolyze the carbamate salt and form N pethylphenylsulfonyl-N'-2-bicyclo[2.2.IJheptylurea. The reaction mixtureafter being cooled was diluted with ether and extracted with 10 percentammonium hydroxide. The basic extract was chilled in an ice bath andacidified by adding dilute hydrochloric acid. The product was extractedinto ether, the ether layer was dried, and the ether was removed undervacuum. The residue was recrystallized from ethanol to giveN-p-ethylphenylsulfonyl-N-2-bicyclo[2.2.1]heptylurea melting at 129- 3 1C.

Analysis-Cale; C, 59.59; H, 6.88; N, 8.69. Found: C, 59.68; H, 6.67; N,8.43.

Example 2 A parallel procedure employing2-bicyclo[2.2.1]heptylmethylamine with ethylN-p-ethylphenylsulfonylcarbamate producedN-p-ethylphenylsulfonyl-N-2-bicyclo- [2.2.1]heptylmethylurea melting at163-5 C. after recrystallization from ethanol.

Analysis.Calc.: C, 60.65; H, 7.19; N, 8.33. Found: C, 60.45; H, 7.20; N,8.23.

Example 3 A solution of 0.5 g. of N-p-ethylphenylsulfonyl-N-2-bicyclo[2.2.1]heptylurea in chloroform was shaken vigorously with aslight excess of a 10 percent aqueous sodium carbonate solution. Thesodium salt of N-p-ethylphenylsulfonyl-N'-2-bicyclo[2.2.1]heptylurea wasprecipitated and was isolated by filtration as a white amorphous solid.

3 We claim: 1. A compound selected from the group consisting ofcompounds of the formula wherein R is 2-bicyclo[2.2.1]heptyl, and thesalts thereof with nontoxic cations.

2. N-p-ethylpheny1sulfonyl-N-2-bicyclo [2.2.1]hepty1- 10 urea.

UNITED STATES PATENTS Haack et a1. Oct. 6, 1959 Aeschlimann et al Mar.15, 1960 Ruschig et a1. Jan. 17, 1961 Wright Jan. 8, 1963 Stroll et a1.June 25, 1963 FOREIGN PATENTS Great Britain Mar. 23, 1960

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 